1. Technical Field
The present disclosure relates to compositions and methods for stimulating auditory neuron growth to prevent or treat hearing loss. In particular, statin compositions are disclosed for stimulating neurite growth from spiral ganglion neurons in the inner ear and methods for preventing damage to or treating damage of auditory neurons and/or hair cells of the cochlea following acoustic or ototoxic insult.
2. Description of Related Art
Continuous exposure to high decibel level acoustic insults or exposure to certain antibiotics or chemical toxins can result in severe inner ear damage, promote hearing impairment and deafness, and ultimately interfere with job performance (for example, Humes L, Joellenbeck L, Durch J (2005) Noise and Military Service: Implications for Hearing Loss and Tinnitus: National Academies Press; Yankaskas K (2013) Prelude: noise-induced tinnitus and hearing loss in the military. Hearing Research 295: 3-8). Recent evidence indicates that there are auditory insults, whose effects were previously unrecognized with standard audiograms, that can initiate an irreversible decay in hearing acuity, but do not cause obvious physical damage to the sound transducing cells (hair cells) in the cochlea. In fact, when one considers these formerly invisible sources of cochlear damage, it is easier to put in perspective the huge financial outlay (over $1 billion per year in FY2013) the U.S. Veterans Administration finds necessary to care for service-related hearing disabilities.
Permanent Threshold Shift (PTS) and Temporary Threshold Shift (TTS)
In the clinical assessment of hearing, “threshold” refers to the lowest sound level that a subject can hear. Physical harm to the ear—such as those induced by blasts, explosions, shock waves and unremitting high decibel noise—causes a permanent elevation in the threshold needed to detect sound (permanent threshold shift, PTS). On the other hand, intense loud sounds of short duration, such as those produced by a period of weapons fire on a range or in combat, or at a music concert, or in close proximity to fireworks or using loud headphones can cause a “temporary” deafness as measured by reversible elevation in the threshold. Because, over time, the elevated threshold returns to normal, the episode is called “temporary threshold shift” or TTS. Until recently, TTS was thought to reflect a transitory damage to hearing, and the return of the threshold to its pre-noise exposure level, was taken as evidence that the subject was “cured”. Recent studies in guinea pigs and mice indicate that this previously misunderstood “temporary” hearing injury is not “temporary” and that results from threshold shift analysis alone fail to reveal serious aspects of hearing damage. In particular neurons that are required to encode acoustic information at higher sound levels are damaged. Therefore, speech recognition in noisy listening environments becomes difficult.
The cochlea is the peripheral organ of hearing (FIG. 1). It lies between the middle ear and the brain. The neurons of the spiral ganglion are situated within the cochlea in a boney pocket close to the axis of the spiral (FIG. 1, blue circle). Spiral ganglion neurons are bipolar, meaning they have two nerve fibers arising from their cell bodies. Hair cells, located at the edge of the cochlear spiral (FIG. 1, green circle; FIG. 2), detect and transduce auditory information. The peripherally oriented nerve fibers (FIG. 3, path A) of the spiral ganglion neurons synapse on hair cells. The centrally oriented nerve fibers (FIG. 3, path B) collect within the cochlea to form the cochlear part of the auditory (VIIIth nerve). These fibers grow to the brain and eventually separate to synapse on nerve cells in the cochlear nucleus.
Auditory information from the periphery is first carried to the brain through this nerve fiber network. Consequently, anything that interferes with the transfer of information (for example, loss of hair cells, loss of neurons, loss of synapses, loss of nerve fibers) will cause hearing loss.
One of the defining elements of auditory information is that of the frequency of sound. The ability to encode frequency information and transmit it to the brain underlies the human ability to interpret pitch and speech. A gradient of sound frequencies is encoded along the spiral of the cochlea, from base to apex. This frequency/place representation of sound (called “tonotopic”) is carried through the spiral ganglion to the brain stem and is preserved up to the auditory cortex (FIG. 4). The more discrete frequencies that can be represented in the ear and carried to the cortex, the better the sound interpretation will be by the listener.
Pathology of Permanent (PTS) and Temporary (TTS) Threshold Shift
PTS is primarily sensorineural in origin and is due to loss of function or degeneration of hair cells or spiral ganglion neurons, neither of which will spontaneously regenerate after damage. After hair cells degenerate in PTS, neurons respond in at least two ways. Some immediately die. In others, the disconnected peripheral fiber (FIG. 3, path A) retracts (degenerates). But the centrally-connected fibers (FIG. 3, path B) degenerate more slowly. This means that even after the loss of the peripheral nerve fiber or synaptic input, the neuron can remain connected to the brain stem in a more or less tonotopic organization.
The only treatments currently available for PTS are hearing aid devices (which depend on preservation of at least some of the neurons and hair cells) or cochlear implant (CI) devices. A CI device consists of a speech processor and an array of electrodes that is inserted into scala tympani of the cochlea. Electrical current is delivered through the electrodes to the tissue to stimulate the remaining spiral ganglion cells. CI device electrodes are aligned along the tonotopically-organized spiral ganglion to model the tonotopic stimulation of the cochlea by acoustical stimuli in a pristine cochlea. Current spreads in the tissue and stimulation at neighboring electrode contacts results in confusing information because the current fields overlap. The further the target neurons are located from the electrode contacts the more current is required for stimulation, which worsens the overlap of the current fields. Hence, current spread in the tissue limits the number of electrodes that can encode discrete frequency information. Various authors have suggested the desirability of intervening to maintain spiral ganglion neuronal survival and/or to stimulate the regrowth of their peripheral neurites.
TTS Differs Significantly from PTS
For TTS, the hair cells do not degenerate after the insult to the ear. Despite the overall preservation of hair cells, a population of synapses between the inner hair cell and spiral ganglion peripheral fibers degenerate irreversibly almost immediately after sound exposure. Fibers synapsing on inner hair cells can be categorized as those that respond to low level sounds and others that respond to high level sound. The fibers that respond to low level tones saturate in their response at sound levels 20-40 dB above their threshold, while some of neurons with high threshold increase their activity over a larger range of sound intensities. Thus, the second type of fiber improves hearing in noisy environments where the neurons that respond to low sound levels are already saturated. In noise-induced TTS, the neurons and synapses that response to high level sound will be damaged. In other words, thresholds to pure tones do not change. The effect of TTS damage is on the ability to encode large ranges of sound levels and the ability to encode sound at higher levels. But the effect is not only on the synapses. TTS insult initiates the inexorable, but previously unknown, degeneration of spiral ganglion neurons over time. The long-term fate of spiral ganglion cells is thought to be sealed within the first 24 hours post exposure (Kujawa S G and Liberman M C (2009) Adding insult to injury: Cochlear nerve degeneration after “Temporary” noise-induced hearing loss. Journal of Neuroscience 29:14077-14085.)
Compounds
A number of compounds have been investigated by others for their ability to effect or maintain neuron growth. These compound studies are summarized below.
(a) Neurotrophins
A variety of reports have shown that two neurotrophins, brain derived neurotrophic factor (BDNF) and neurotrophic factor 3 (NT3) will maintain neuronal survival in vivo as long as they are continuously applied to the cochlea. To provide a continuous supply of growth factors, various studies have attempted to biologically generate NT3 or BDNF with the use of genetically engineered viruses or genetically modified “cell factories”. Success has been limited and has been dependent on the time after deafness that treatment is initiated, the cell types that undergo transduction, the concentrations of neurotrophins that the cell factories can generate in the ear, and the length of time that they are producing sufficient amounts of the neurotrophins. A few studies in vivo have suggested that neurotrophins can also stimulate neurite growth, but this stimulation does not seem to be robust and the design of the experiments have not clearly differentiated effects on neuronal survival, neurite repair, neurite source (local or from the brain) and neurite branching. Neurotrophin studies have provided valuable information on spiral ganglion cell survival and given insight into mechanisms for nearly 20 years, but they have not led to drugs for use in the ear.
(b) Antioxidants
The effects of antioxidant related compounds on the cochlea and on hearing after noise exposure have been reported. Hair cells can be partly protected from the initial effects of noise, if certain antioxidant(s) are provided before, during and after the noise insult. There is also some data that suggests that certain antioxidants may have some protective effect on neurons, although there is no information on the specific effects of antioxidants on neurite growth.
(c) Other Compounds
Several other biological factors have been tested for effects on hearing, hair cells and/or neurons. These include GDNF, βFGF, erythropoietin, lithium, Bone morphogenetic protein (BMP) 2; (BMP4), depolarization, cpt-cAMP, leukemia inhibitory factor. These factors may shed light on biochemical pathways important to survival and neurite growth of spiral ganglion neurons. Lie M, Grover M, Whitlon D S (2010) Accelerated neurite growth from spiral ganglion neurons exposed to the Rho kinas inhibitor H1152. Neuroscience 169: 855-862 demonstrated that the Rho kinase inhibitor H1152 can stimulate neurite growth from spiral ganglion neurons in vitro, being the first demonstration that inhibiting the activity of an enzyme would increase neurite length from spiral ganglion neurons.
Past PTS studies demonstrated that the central fibers of spiral ganglion neurons degenerate more slowly than peripheral fibers. Thus, the tonotopic orientation can be more or less maintained in the brain even after the peripheral synapses (and thus transfer of information from the hair cells to the neurons) are lost. Yet no compounds exist for maintaining spiral ganglion neurons and stimulating the regeneration of their nerve fibers and synapses. Consequently, no known compositions are available that are suitable for preventing or treating auditory neuron damage of the cochlea and acquired deafness. There is a need for such compositions and methods.